1-NA-PP1

1-NA-PP1 is a reversible, cell-permeable inhibitor of Src-family tyrosine kinases that have been mutated, by a single base substitution, to become ‘analog sensitive’ (as), as compared to the wild-type kinase. 1-NA-PP1 was first developed to optimally inhibit v-Src-as1, with an I338G substitution, preferentially over v-Src (IC₅₀ = 1.5 nM versus 1.0 μM, respectively).¹ The homologous mutation in other kinases generated similar analog sensitivity (e.g., IC₅₀ = 1.5 nM for c-Fyn-as1 versus 0.6 μM for c-Fyn; 7.0 nM for c-Abl-as2 versus 0.6 μM for c-Abl; 15 nM for Cdk2-as1 versus 18 μM for Cdk2).² This approach has been used to elucidate functions of several kinases in both mammalian and yeast systems.^2,3,4

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1. Bishop, A.C., Kung, C.y., Shah, K., et al. Generation of monospecific nanomolar tyrosine kinase inhibitors via a chemical genetic approach. J. Am. Chem. Soc. 121(4), 627-631 (1999).

2. Bishop, A.C., Ubersax, J.A., Petsch, D.T., et al. A chemical switch for inhibitor-sensitive alleles of any protein kinase. Nature 407(6802), 395-401 (2000).

3. Endo, S., Satoh, Y., Shah, K., et al. A single amino-acid change in ERK1/2 makes the enzyme susceptible to PP1 derivatives. Biochem. Biophys. Res. Commun. 341(1), 261-265 (2006).

4. Kenski, D.M., Zhang, C., von Zastrow, M., et al. Chemical genetic engineering of G protein-coupled receptor kinase 2. The Journal of Biological Chemisty 280(41), 35051-35061 (2005).